2-(3-Substituted amino-2-hydroxypropoxy)-3-substituted pyrazines

ABSTRACT

2-(3-Substituted amino-2-hydroxypropoxy)-3-substituted pyrazine compounds optionally having substituents in the 5 and/or 6 positions, possessing  beta -adrenergic blocking properties are described. The products are prepared by reaction of a 2-chloro(or hydroxy)pyrazine with a 5-hydroxy-methyl(or sulfonyloxymethyl)oxazolidine followed by acid hydrolysis.

This application is a division of pending application Ser No. 408,032,filed Oct. 19, 1973 now U.S. Pat. No. 3,946,009, which in turn is acontinuation-in-part of application Ser. No. 341,421, filed Mar. 15,1973, now abandoned.

This invention is concerned with 2-(3-substitutedamino-2-hydroxypropoxy)-3-substituted pyrazine compounds which canoptionally be substituted in the 5 and 6 positions and which existseither in the form of racemic mixtures or as optionally active isomersthereof particularly the isomer in the sinister configuration whichcompounds exhibit β-adrenergic blocking properties.

The novel pyrazine compounds of this invention have the structure##STR1## as well as pharmacologically acceptable salts thereof wherein Rrepresents C₁₋₅ alkyl, phenyl, substituted phenyl wherein thesubstituent is C₁₋₃ alkyl (preferably methyl), C₁₋₃ alkoxy (preferablymethoxy and ethoxy), amino, nitro, or halo (preferably chloro, bromo, orfluoro), phenyl-C₁₋₃ alkyl, (preferably benzyl), hydroxyphenyl-C₁₋₃alkyl (advantageously hydroxybenzyl), C₂₋₅ alkoxyalkyl, C₅₋₇ cycloalkyl,C₁₋₃ alkoxy, phenoxy, or substituted phenoxy where the substituents arethe same as those described above for attachment to the phenylsubstituent, benzyloxy optionally having an alkyl, alkoxy, nitro, aminoor halo substituent attached to the phenyl moiety of the type describedabove for attachment to the phenyl substituent, or a 5- to 7-memberedN-containing heterocycle which optionally can contain as additionalhetero atoms an oxygen, sulfur or one or two additional nitrogen atoms,said N-containing heterocycle advantageously being 1-pyrrolidinyl,piperidino, hexahydrozepinyl, morpholino, thiomorpholino, imidazolyl,pyrazolyl, and triazolyl; R¹ represents a straight or branched chainC₃₋₆ alkyl, a straight or branched chain hydroxy substituted C₃₋₆ alkyl,a straight or branched chain C₃₋₆ alkinyl, phenyl-C₁₋₆ alkyl orindolyl-C₁₋₆ alkyl; R² and R³ can represent the same or differentsubstituents and represent hydrogen, C₁₋₃ alkyl, C₅₋₇ cycloalkyl, C₁₋₃alkoxy, phenoxy, phenyl, substituted phenyl wherein the substituents arethe same as identified for the phenyl substituents in the definition ofvariable radical R, amino, acylamino (preferably acetylamino), and a 5-to 7-membered N-containing heterocyclic substituent of the type andvariety described in the definition of R substituent, supra.

Suitable pharmacologically acceptable salts of product I are acidaddition salts derived from inorganic acids, for example,hydrochlorides, hydrobromides, phosphates, or sulfates or salts derivedfrom organic acids, for example, oxalates, lactates, malates, maleates,formates, acetates, succinates, tartrates, salicylates, citrates,phenylacetates, benzoates, p-toluenesulfonates and other salts such asthose that provide relatively insoluble products that afford a slowrelease of the active material, for example, a1,1'-methylene-bis(2-hydroxy-3-naphthoate) and the like.

The novel products, I, as well as their intermediates which contain oneasymmetric carbon in the propylene chain will be obtained either as aracemic mixture which can be separated into optically active isomers byknown methods or the sinister isomer can be directly obtained by use ofan appropriate optically active oxazolidine in its sinisterconfiguration. One suitable method for separating the racemic mixtureinvolves formation of a salt thereof with an optically active acid, manyof which are known to those skilled in the art, such as optically activetartaric, mandelic, cholic, 0,0-di-p-toluoyl tartaric, 0,0-di-benzoyltartaric acids or other acids conventionally employed for this purpose.Spontaneous resolution can also be considered a means for separating theoptically active isomers.

The potential of a product as a β-adrenergic blocking agentconventionally is evaluated by the protocol which was employed to assessthe β-blocking properties of the novel compounds of this invention. Theprotocol employed comprises intravenous administration of graded dosesof the selected compound to rats which then are challenged with astandard dose of isoproterenol, a product known to be a β-stimulant.

The clinical application of β-adrenergic blocking agents is well knownto physicians. Uses for the novel products of this invention includetreatment of angina pectoris, use in hypertension with or without otherhypertensive drugs, control of tachycardia or cardiac arrhythmias due toexcess catecholamines. In view of the considerable amount of literaturethat has accumulated concerning the use of β-adrenergic blocking agents,physicians would employ the products of this invention in any of theknown conditions where a β-blocker is needed, such as in the managementof angina pectoris.

The products can be prepared in pharmaceutical formulations suitable fororal or parenteral administration preferably in the form of tablets,solutions, suspensions or emulsions using well known techniques andexcipients, diluents, lubricants, and the like. Dosage units of fromabout 1 mg. to about 40 mgs. can be provided for the symptomaticadjustment of dosage by the physician depending upon the age andcondition of the patient.

The novel pyrazine products, I, of this invention advantageously can beprepared by the synthesis schematically illustrated below: ##STR2## Thepyrazine compound II is reacted with the oxazolidine, III, to give theoxazolidine adduct, IV, which when treated with mineral acid provides,the desired end product, I.

When R⁴ in the pyrazine, II, is chloro or bromo, this compound isreacted with an oxazolidine, III, wherein R⁵ is hydrogen. The reactionis carried out in the presence of a strong base and preferably atambient temperature although the reaction mixture either can be heatedup to reflux or cooled to 0° C. A solvent for the reactants is desirableand any conventional solvent can be employed for this purpose, suitableones being lower alkanols or polar aprotic solvents such asdimethylformamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran(THF), hexamethylphosphoramide (HMP), and the like. The readilyavailable and relatively inexpensive tert-butanol has been found to be aquite suitable, general purpose solvent for these intermediates. Strongbases that are recommended for use in the reaction are alkali metalalkoxides or alkali metal hydroxides, preferably the sodium or potassiumalkoxides or hydroxides or sodium hydride. When the S-isomer of theoxazolidine is employed in the reaction one obtains product I in itssinister configuration. When the oxazolidine employed is not opticallyactive, then the end product is obtained as a racemix mixture which canbe separated by any of the conventional methods employed for thispurpose.

When R⁴ in the pyrazine starting material, II, represents a hydroxygroup then R⁵ in the oxazolidine is a sulfonyl group. These reagents arecoupled advantageously by combining the reactants in the presence of astrong base and a solvent, such as those described above, to form theintermediate IV which upon treatment with mineral acid provides thedesired product I. Heating the reaction mixture up to the refluxtemperature can be employed if desired and any of the usual organicsolvents can be used especially selected from those identified above.When the oxazolidine reagent, III, is the optically active compound inthe sinister configuration then the end product I is obtained in itssinister configuration also. Racemic III provides the end product I inits racemic form also which can be separated, if desired, by any of theconventional methods employed for this purpose.

When end product I in the form of the free base is obtained as an oil,crystalline material can be prepared by forming a salt thereof by knownmethods. Suitable salts are those formed with mineral acids or organicacids such as, for example, the hydrochloride salt, the sulfate salt,the hydrogen maleate salt, or other desired mineral or organic acidsalt.

Preparation of the Oxazolidine Starting Substances, III

The oxazolidine reagent, III, either as a racemic mixture or as theS-isomer can be prepared by published procedures by reacting1,2-dihydroxy-3-substituted aminopropane or a1-sulfonyloxy-2-hydroxy-3-substituted aminopropane with an aldehyde, R⁶CHO, to provide the oxazolidine of structure III. When the S-isomer ofthe aminoalkanols are employed in the preparation of the oxazolidine itis obtained in its sinister configuration whereas racemic startingmaterials give racemic oxazolidines which themselves can be resolvedinto their optically active components. The aldehyde used in thepreparation of the oxazolidine is not critical as any aldehyde can beused in the formation of the cyclic structure which subsequently iscleaved by acid hydrolysis to remove the ##STR3## grouping provided bythe aldehyde. For practical purposes, any commercially available andinexpensive aldehyde can be employed and among these there can bementioned aliphatic aldehydes, alicyclic, aromatic or heterocyclicaldehydes such as formaldehyde, lower alkyl aldehydes, benzaldehyde,phenyl-lower alkyl aldehydes, and the like, the phenyl moiety of eitherof the latter aldehydes optionally having one or more similar ordissimilar substituents selected from halogen, lower alkyl, haloalkyl,amino, acylamino, mono- or di-alkylamino, nitro, alkoxy, phenalkoxy,haloalkoxy, and hydroxy, a heterocyclic aldehyde optionally havingsubstituents as halogen, lower alkyl, phenalkyl and the like. Among themany aldehydes that can be employed there can be mentioned formaldehyde,acetaldehyde, propionaldehyde, butyraldehyde, phenylacetaldehyde,anisaldehyde, benzaldehyde, mesitaldehyde, tolualdehyde, furfural andthe like.

As mentioned above, R⁵ can be hydrogen or an alkyl-, aryl-, oraralkyl-sulfonate. Again the particular sulfonyl group is not criticalas any sulfonyl substituent that replaces the hydrogen of the 1-hydroxylgroup of the 1,2-dihydroxy-3-substituted aminopropane or that replacesthe hydrogen of the 5-hydroxyl group of the 5-hydroxymethyloxazolidinewill activate these former hydroxyl substituents. For practicalpurposes, commercially available and inexpensive sulfonyl halides wouldbe employed for this purpose and these would fall into the class ofalkylsulfonyl halides and benzenesulfonyl halides wherein the benzenemoiety can optionally be substituted with one or more similar ordissimilar substituents, selected from lower alkyl, lower alkoxy, halo,amino, and nitro substituents. Among the commercially available sulfonylhalides that can be employed for this purpose there can be mentionedmethanesulfonyl chloride, benzenesulfonyl chloride, nitrobenzenesulfonylfluoride, trichlorobenzenesulfonyl chloride, tribromobenzenesulfonylchloride, fluorobenzenesulfonyl chloride, 4-chloro-2-(or3)-nitrobenzenesulfonyl chloride, hexadecanesulfonyl chloride,2-mesitylenesulfonyl chloride, methoxybenzenesulfonyl chloride and thelike.

While many oxazolidine compounds of structure III are known compounds,the following procedures provide illustrative methods that arerepresentative of feasible means for making those compounds that are notreadily available commercially or which may be novel members required tointroduce the desired 3-amino-2-hydroxypropoxy substituent in the2-position of end product I.

Method 1-A: Preparation of a 5-hydroxymethyl-2-R⁶ -3-R¹ -oxazolidinePreparation 1: S-3-(1-methyl-2-phenethyl)-5-hydroxymethyl-oxazolidine

Step A: S-1,2-dihydroxy-3-(1-methyl-2-phenethylamino)propane

A mixture of 1-methyl-2-phenethylamine (0.513 mole), methanol (150 ml.)and 5% palladium-on-carbon (1.0 g.) is shaken in a hydrogenation bombunder three atmospheres hydrogen pressure. A solution ofD-glyceraldehyde (15 g.) in methanol (60 ml.) is added over a one hourperiod during hydrogenation. After the addition, the mixture is skakenfor an additional 15 hours. The catalyst is removed by filtration andthe solvent evaporated in vacuo yieldingS-1,2-dihydroxy-3-(1-methyl-2-phenethylamino)propane.

By replacing the 1-methyl-2-phenethylamine employed in Step A by anequivalent quantity of 1-methyl-2-(2-indolyl)ethylamine and followingsubstantially the same procedure described in Step A, there is obtainedS-1,2-dihydroxy-3-[1-methyl-2-(2-indolyl)ethylamino]propane.

Step B: S-3-(1-methyl-2-phenethyl)-5-hydroxymethyloxazolidine

A mixture of S-1,2-dihydroxy-3-(1-methyl-2-phenethylamino)propane (0.2mole), aqueous formaldehyde (20 ml. of 37% solution) and benzene (80ml.) is heated under reflux with continuous removal of water for twohours. The solvent then is evaporated in vacuo (15 mm. pressure)providing S-3-(1-methyl-2-phenethyl)-5-hydroxymethyloxazolidine.

When an S-1-sulfonyloxy-2-hydroxy-3-(1-methyl-2-phenethylamino) propaneis reacted with formaldehyde by the procedure described in Step B thereis obtained S-3-(1-methyl-2-phenethyl)-5-hydroxymethyl-oxazolidine.

Method 1-B: Preparation of a 5-sulfonyloxymethyl-2-R⁶ -3-R¹ -oxazolidinePreparation 2: Preparation ofS-3-(1-methyl-2-phenethyl)-5-(benzenesulfonyloxymethyl)oxazolidine

To a solution of S-3-(1-methyl-2-phenethyl)-5-hydroxymethyloxazolidine(10 mmole), prepared as described in Procedure 1, Steps A and B, inpyridine (3ml.) there is added benzenesulfonyl chloride (10 mmole) andthe mixture stirred for about 1 hour at 25° C. Ether (20 ml.) is addedwhereuponS-3-(1-methyl-2-phenethyl)-5-(benzenesulfonyloxymethyl)oxazolidinehydrochloride is precipitated, removed by filtration and washed wellwith ether and dried in vacuo at 40° C.

Any of the needed oxazolidine reactants, structure III, can be made byPreparations 1 and 2 by replacing the 1-methyl-2-phenethylamine inProcedure 1, Step A by a required amine to yield the --NHR¹ substituentand reacting the dihydroxy-propylamine thus formed with any aldehyde ofstructure R⁶ CHO to provide the 5-hydroxymethyl oxazolidine. Thisproduct then can conveniently be converted to the5-sulfonyloxymethyloxazolidine by reaction with any sulfonyl chloride asdescribed in Preparation 2. Representative oxazolidines that can be madeby these procedures are identified in Table I.

                  TABLE I                                                         ______________________________________                                        R.sup.1 NH.sub.2 + D(orDL)glyceraldehyde +                                     ##STR4##                                                                      ##STR5##                                                                      ##STR6##                                                                      ##STR7##                                                                      ##STR8##                                                                     ______________________________________                                        Pre-                                                                          paration                                                                      No.    R.sup.1           R.sup.6 R.sup.5'                                     ______________________________________                                        3      1-methyl-2-(3-indolyl)ethyl                                                                     H       phenyl                                       4      Tert.-butyl       phenyl  p-tolyl                                      5      Tert.-butyl       H       p-tolyl                                      6      Tert.-butyl       H       p-bromophenyl                                7      i-propyl          H       phenyl                                       8      2,2-dimethylpropyl                                                                              H       methyl                                       9      1,1-dimethyl-2-hydroxyethyl                                                                     H       p-cholorophenyl                              10     1,1-dimethyl-2-phenethyl                                                                        H       phenyl                                       11     1,1-dimethyl-2-(2-indolyl)-                                                                     H       p-tolyl                                             ethyl                                                                  12     2,2-dimethyl-2-(3-indolyl)-                                                                     H       phenyl                                              ethyl                                                                  ______________________________________                                    

Preparation of the Pyrazine Starting Substances, II

Many pyrazine staring substances of structure II have been described inthe literature, any of which can be reacted with the appropriateoxazolidine (III) as discussed above to give the desired end product I.Some representative methods that can be employed for making any desiredpyrazine that may not be readily available commercially are depictedbelow along with one or more examples to provide information concerningthe working conditions suitable for carrying out each procedure.

Method 2: Preparation of 2-R⁴ -3-R-5-R³ -6-R² -Pyrazines ROUTE IPARTICULARLY SUITABLE WHEN

R is alkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, orcycloalkyl

R³ is hydrogen, alkyl, cycloalkyl, phenyl, or substituted phenyl and

R² is hydrogen, alkyl, cycloalkyl or phenyl ##STR9##

The following reaction is typical for the above sequence.

Preparation 13: 2-Chloro-3-p-methoxyphenylpyrazine

Step A: 2-Hydroxy-3-p-methoxyphenylpyrazine

p-Methoxyphenyl glycinamide (0.10 mole) in 125 ml. Methanol cooled to-30° C. is treated with a solution of 19.3 g. (0.10 ml.) of 30% glyoxalin 25 ml. methanol also precooled to -30° C. The mixture is stirred andadded dropwise during 15-30 minutes to 10 ml (0.125 mole) of 12.5 Naqueous sodium hydroxide, the temperature of the reaction mixture beingheld at -20° to 15° C. during this addition. The mixture is refrigerated1-2 hours at -10° C., then 1 hour at -2° to 3° C., whereupon there isadded 12 N HCl followed by 5 g. solid sodium bicarbonate to neutralizeany excess acid. The solution then is evaporated to dryness and theresidue extracted with chloroform. The extracts are evaporated and theproduct crystallized from a suitable solvent mixture, i.e.chloroform-methanol to give 2-hydroxy-3-p-methoxyphenylpyrazine.

Step B: 2-chloro-3-p-methoxyphenylpyrazine

The 2-hydroxy-3-p-methoxyphenylpyrazine is refluxed (120°-130° C.) withexcess phosphorus oxychloride under stirring for 3-5 hours. The solutionis evaporated to dryness at 50° C. in vacuo, cooled, ice is added, thentreated with 10% sodium hydroxide solution, extracted with a suitablesolvent such as diethyl ether, the ethereal solution washed with waterand evaporated. The crude product is crystallized from a suitablesolvent such as ethanol to give 2-chloro-3-p-methoxyphenylpyrazine.

The following procedure provides a feasible method for making theglycinamide reactant should this starting substance not be readilyavailable.

Preparation 14: 2-Chloro-3-p-methylphenypyrazine

Step A: p-Methylphenylglycinamide

p-Methylphenylglycine is dissolved in excess 6 N HCl and evaporated todryness. This residue in the cold is dissolved in excess thionylchloride and after standing at 20° C. for 1-2 hours is evaporated todryness and the acid chloride hydrochloride is treated with aqueousammonia for several hours to give 3-p-methylphenylglycinamide which iscrystallized from a suitable solvent such as ethanol.

Step B: 2-Hydroxy-3-p-methylphenylpyrazine

By replacing the p-methoxyphenyl glycinamide employed in Procedure 13, Aby an equivalent quantity of p-methylphenylglycinamide and followingsubstantially the same procedure as described in Procedure 13, A thereis obtained 2-hydroxy-3-p-methylphenylpyrazine.

Step C: 2-chloro-3-p-methylphenylpyrazine

By replacing the 2-hydroxy-3-phenylpyrazine employed in Procedure 13, Bby an equivalent quantity of 2-hydroxy-3-p-methylphenylpyrazine andfollowing substantially the same procedure as described in Procedure 13,B there is obtained 2-chloro-3-p-methylphenylpyrazine.

Preparation 15: 2-Chloro-3-cyclopentylpyrazine

By replacing the p-methylphenylglycine employed in Procedure 14, Step Aby an equivalent quantity of cyclopentylglycine, there is obtainedcyclopentylglycinamide. Substituting this cyclopentylglycinamide forthat employed in Procedure 13 and following the methods described inSteps A and B of Procedure 13, there is obtained in Step A2-hydroxy-3-cyclopentylpyrazine and in Step B2-chloro-3-cyclopentylpyrazine.

Similarly, by replacing the p-methylphenylglycine in Step A of Procedure14 by

16: p-nitrophenylglycine

17: p-aminophenylglycine

and in each instance following the methods described in Steps A-C ofProcedure 14, there is obtained, respectively

Preparation 16

Step B: 2-Hydroxy-3-p-nitrophenylpyrazine

Step C: 2-Chloro-3-p-nitrophenylpyrazine

Preparation 17

Step B: 2-Hydroxy-3-p-aminophenylpyrazine

Step C: 2-Chloro-3-p-aminophenylpyrazine

Additional pyrazines (II) that are advantageously prepared by Route Iare identified in Table II wherein the variable substituents R³, R², andR in the glyoxal (or α, β-diketone), glycinamide and in the pyrazines Aand B are the groups identified in the table.

                  TABLE II                                                        ______________________________________                                        Prepara-                                                                      tion No.                                                                             R.sup.3       R.sup.2   R                                              ______________________________________                                        18     methyl        H         methyl                                         19     methyl        methyl    methyl                                         20     phenyl        H         methyl                                         21     phenyl        methyl    propyl                                                methyl        phenyl    propyl                                         22     methyl        methyl    methyl                                         23     H             H         p-hydroxyphenyl                                24     H             H         p-methoxyphenyl                                25     H             H         p-chlorophenyl                                 26     methyl        H         p-hydroxbenzyl                                 27     methyl        methyl    p-hydroxybenzyl                                28     H             H         cyclohexyl                                     29     H             H         benzyl                                         30     phenyl        phenyl    benzyl                                         31     phenyl        H         benzyl                                         32     p-methylphenyl                                                                              H         phenyl                                         33     p-methoxyphenyl                                                                             H         phenyl                                         34     p-chlorophenyl                                                                              H         phenyl                                         35     p-nitrophenyl H         phenyl                                         36     o-hydroxyphenyl                                                                             H         phenyl                                         37     m-hydroxyphenyl                                                                             H         phenyl                                         38     p-hydroxyphenyl                                                                             H         phenyl                                         39     cyclohexyl    H         benzyl                                         40     cyclopentyl   H         benzyl                                         41     cyclohexyl    cyclohexyl                                                                              phenyl                                         42     pyridyl       pyridyl   methyl                                         ______________________________________                                    

ROUTE II PARTICULARLY SUITABLE WHEN

R is alkoxy, phenoxy (or substituted), benzyloxy (or substituted), orN-heterocyclic

R² is H or alkoxy and wherein

R² = R³ = alkyl or phenyl ##STR10##

The following reactions are typical for the above sequence:

Preparation 43: 2-Chloro-3-methoxypyrazine

A mixture of 0.1 mole of 2,3-dichloropyrazine and 2.3 g. (0.1 mole) ofsodium in 160 ml. of anhydrous methanol is refluxed 5-10 hours, andpoured into water. The product is extracted with ether or chloroform andrecrystallized from a suitable solvent such as ethanol to give pure2-chloro-3-methoxypyrazine.

Preparation 44: 2-Chloro-3-phenoxypyrazine

A suspension of 0.1 mole of sodium phenoxide and 0.1 mole2,3-dichloropyrazine is refluxed 10-20 hours. The cooled mixture isextracted with diethyl ether, washed with cold 2 N sodium hydroxidesolution, dried, and evaporated to give 2-chloro-3-phenoxypyrazine.

Preparation 45: 2-Chloro-3-benzyloxypyrazine

Sodium hydride (0.10 mole) is added to 0.10 mole of benzyl alcohol in100 ml. dry benzene and the mixture is refluxed 1-2 hours. The cooledsolution is treated with 0.10 mole of 2,3-dichloropyrazine in 100 ml. ofbenzene. The mixture is refluxed for 20-60 hours, cooled, washed withwater, dried, and evaporated and the product distilled in vacuo to give2-chloro-3-benzyloxypyrazine.

Preparation 46: 2-Chloro-3-morpholinopyrazine

A mixture of 2,3-dichloropyrazine (5 g., 0.034 mmole), morpholine (5.8g., 0.067 mmole), and 50 ml. of dimethylformamide are heated at 90°-120°C. for 6-14 hours, in an atmosphere of nitrogen. The reaction mixture iscooled and evaporated to dryness at a water-bath temperature of 55° C. Achloroform solution of the residue is extracted twice with 0.1M sodiumhydroxide, dried over magnesium sulfate and evaporated to leave theproduct.

Other 2-chloro-3-(N-hetero)pyrazines that are advantageously prepared byRoute II, Preparation 46 are identified in Table III wherein2,3-dichloropyrazine is reacted with the N-heterocycle identified incolumn 2 which displaces the 3-chloro by the radical identified incolumn 3.

                  TABLE III                                                       ______________________________________                                        Preparation No.                                                                           N-heterocycle   R                                                 ______________________________________                                        47          pyrrole       pyrrolidinyl                                        48          piperidine    piperidino                                          49          hexahydroazepine                                                                            hexahydroazepinyl                                   50          pyrazole      pyrazolyl                                           51          imidazole     imidazolyl                                          52          triazole      triazolyl                                           53          thiomorpholine                                                                              thiomorpholino                                      ______________________________________                                    

By replacing the 2,3-dichloropyrazine employed in Preparation 46 by

54: 2,3-dichloro-5,6-dimethylpyrazine and

55: 2,3-dibromo(or dichloro)-5,6-diphenylpyrazine

there is obtained, respectively:

Preparation 54: 2-chloro-3-morpholino-5,6-dimethylpyrazine and

Preparation 55: 2-bromo(or chloro)-3-morpholino-5,6-diphenylpyrazine.

A 2-chloropyrazine described in the prior literature that is a usefulintermediate is

2-Chloro-3-methoxymethyl-6-methoxypyrazine.

ROUTE III PARTICULARLY SUITABLE WHEN

R is alkyl or phenyl and

R³ is alkyl or phenyl (or substituted), cycloalkyl, N-heterocyclic##STR11##

The reaction conditions for preparing the 2-hydroxypyrazine A areprovided in detail by Sharp et al in J. Chem. Soc., 1951, 932-934, whichis incorporated herein by reference.

Preparation 56: 2-Chloro-3,5-dimethylpyrazine

These workers described the preparation of

2-hydroxy-3,5-dimethylpyrazine

which can be treated with phosphorus oxychloride by the method describedin Preparation 13, Step B, to provide the desired2-chloro-3,5-dimethylpyrazine.

Sharp et al, supra, describe the preparation of

2-amino-3-methyl-5-ethylpyrazine 1-oxide,

2-amino-3-phenyl-5-methylpyrazine 1-oxide and

2-amino-3-methyl-5-phenylpyrazine 1-oxide

each of which can be converted by the methods described in the J. Chem.Soc. paper to the

2-hydroxy-3-methyl-5-ethylpyrazine,

2-hydroxy-3-phenyl-5-methylpyrazine, and

2-hydroxy-3-methyl-5-phenylpyrazine.

These compounds, in turn, can be reacted with phosphorus oxychloride byPreparation 13, Step B, method to give

Preparation 57: 2-chloro-3-methyl-5-ethylpyrazine

Preparation 58: 2-chloro-3-phenyl-5-methylpyrazine

Preparation 59: 2-chloro-3-methyl-5-phenylpyrazine.

Other pyrazines advantageously prepared by Route III are identified inTable IV wherein the variable substituents R and R³ in the oxime,nitrile, 2-aminopyrazine-1-oxide, 2-aminopyrazine and the pyrazines Aand B are identified in the table.

                  TABLE IV                                                        ______________________________________                                        Preparation No.                                                                             R         R.sup.3                                               ______________________________________                                        60            methyl   phenyl                                                 61            methyl   p-chlorophenyl                                         62            methyl   p-bromophenyl                                          63            methyl   methyl                                                 64            methyl   methoxy                                                65            methyl   p-nitrophenyl                                          66            methyl   p-dimethylaminophenyl                                  67            methyl   cyclohexyl                                             68            methyl   4-pyridyl                                              69            phenyl   3-pyridyl                                              ______________________________________                                    

ROUTE IV PARTICULARLY SUITABLE WHEN

R is alkyl, phenyl, or cycloalkyl

R² is alkyl, phenyl, or cycloalkyl ##STR12##

The procedural details for preparing 2-hydroxypyrazines (A) by thismethod are provided in a paper by Baxter et al, J. Chem. Soc., 1947,370-372, which discussion is included herein by reference.

Preparation 70: 2-Chloro-3,6-dimethylpyrazine

The 2-hydroxy-3,6-dimethylpyrazine disclosed by Baxter et al can bereacted with phosphorus oxychloride by the method described inPreparation 13, Step B, to provide 2-chloro-3,6-dimethylpyrazine.

Preparation 71: 2-Chloro-3-phenyl-6-methylpyrazine

By employing α-bromo-α-phenylacetyl chloride (prepared by treatingα-bromo-α-phenylacetic acid with PBr₃) in place of the 2-bromopropionylbromide used by Baxter et al, supra, and following his method asdepicted above, there is obtained 2-hydroxy-3-phenyl-6-methylpyrazinewhich when treated with phosphorus oxychloride by the method describedin Example 13, Step B, 2-chloro-3-phenyl-6-methylpyrazine is obtained.

Varying the R and R² substituents in the starting materials otherdesired pyrazines A and B can be made particularly those identified inthe heading of Route IV.

ROUTE V PARTICULARLY SUITABLE WHEN

R is alkoxy, phenoxy (or substituted), benzyloxy (or substituted) orN-heterocyclic

R³ is alkyl, alkoxy, phenyl ##STR13##

The following reactions are typical for the above sequence:

Preparation 72: 2-Chloro-3-n-propoxy-5-methylpyrazine

Step A: 2-Amino-3-bromo-5-methylpyrazine

To acetic acid (1500 ml.), 2-amino-5-methylpyrazine (1 mole) and 326.5g. sodium acetate trihydrate are slowly added 1.1 mole bromine in 180ml. acetic acid at 2° C. in the absence of light. The mixture is stirredabout 15 hours at 20° C., stripped of acetic acid in vacuo, poured intoice, made alkaline with sodium hydroxide, filtered, the residueextracted with ether, the extract stripped and the2-amino-3-bromo-5-methylpyrazine crystallized from a suitable solvent.

Step B: 2-Chloro-3-n-propoxy-5-methylpyrazine

By replacing the 2,3-dichloropyrazine and anhydrous methanol used inPreparation 43 by equivalent quantities of the product of Step A andn-propanol and following the method described in Preparation 43,2-amino-3-n-propoxy-5-methylpyrazine is obtained. The 2-amino group canbe converted to the 2-hydroxy by the method described in Sharp et al,ibid., (see Route III) which when treated with phosphorus oxychloride bythe method of Preparation 13, Step B, provides2-chloro-3-n-propoxy-5-methylpyrazine.

Preparation 73: 2-Chloro-3-phenoxy-5-ethylpyrazine

2-Amino-5-ethylpyrazine is brominated as described in Preparation 72,Step A, to provide 2-amino-3-bromo-5-ethylpyrazine. By replacing the2,3-dichloropyrazine used in Preparation 44 by an equivalent quantity of2-amino-3-bromo-5-ethylpyrazine and following substantially the samemethod, there is obtained 2-amino-3-phenoxy-5-ethylpyrazine. The 2-aminogroup is converted to the 2-hydroxy by the method described by Sharp etal, ibid., (see Route III) which when treated with phosphorusoxychloride by Preparation 13, Step B method, there is obtained2-chloro-3-phenoxy-5-ethylpyrazine.

Preparation 74: 2-Chloro-3-benzyloxy-5,6-dimethylpyrazine

The known 2-amino-5,6-dimethylpyrazine can be brominated by Preparation72, Step A method, and then reacted with benzyl alcohol by Preparation45 method to provide 2-amino-3-benzyloxy-5,6-dimethylpyrazine. The2-amino group is converted to the 2-hydroxy by the method described bySharp et al, ibid., (see Route III) which when treated with phorphorusoxychloride by Preparation 13, Step B method, there is obtained2-chloro-3-benzyloxy-5,6-dimethylpyrazine.

Preparation 75: 2-Chloro-3-morpholino-5-phenylpyrazine

2-Amino-5-phenylpyrazine is brominated as described in Preparation 72,Step A, to provide 2-amino-3-bromo-5-phenylpyrazine. By employing anequivalent quantity of this pyrazine for the 2,3-dichloropyrazine inPreparation 46 and following substantially the method described therein,2-amino-3-morpholino-5-phenylpyrazine is obtained. The 2-amino group isconverted to the 2-hydroxy by the method described by Sharp et al,ibid., (see Route III) which when treated with phosphorus oxychloride byPreparation 13, Step B method, there is obtained2-chloro-3-morpholino-5-phenylpyrazine.

By following the procedure of Preparation 75 and employing a2-aminopyrazine having the 5-R³ substituent identified in column 2 andthe N-heterocycle in column 3 the pyrazines A and B having the R³ and Rsubstituents identified in Table V are obtained.

                  TABLE V                                                         ______________________________________                                        Preparation       Heterocyclic                                                No.      R.sup.3  Reactant       R                                            ______________________________________                                        76       methoxy  piperidine   piperidino                                     77       methyl   hexahydroazepine                                                                           hexahydroazepinyl                              78       phenyl   imidazole    imidazolyl                                     79       ethyl    thiomorpholine                                                                             thiomorpholino                                 80       methyl   triazole     triazolyl                                      ______________________________________                                    

ROUTE VI PARTICULARLY SUITABLE WHEN

R is alkoxy, phenoxy (or substituted), benzyloxy (or substituted) orN-heterocyclic ##STR14##

The following reactions are typical for this sequence:

Preparation 81: 2-Chloro-3-butoxy-6-methoxypyrazine

Step A: 2-Chloro-6-methoxypyrazine 4-oxide

Hydrogen peroxide (1.5 ml. of 30%) is added to a solution of 10 mmole of2-chloro-6-methoxypyrazine in 5 ml. acetic acid. The solution is heatedat 60°-75° C. for 10-15 hours. The solution is concentrated to quartervolume, diluted with water and extracted with chloroform, washed, driedand evaporated to give 2-chloro-6-methoxypyrazine 4-oxide which may becrystallized from a suitable solvent such as ethanol.

Step B: 2-Amino-6-methoxypyrazine 4-oxide

2-Chloro-6-methoxypyrazine 4-oxide is treated with an excess of ammoniumhydroxide in an autoclave at 150° C. for 14 hours. The reaction mixtureis cooled and evaporated to dryness to give the crude product which maybe used in the next step as is.

Step C: 2-Amino-3-chloro-6-methoxypyrazine

A suspension of 2-amino-6-methoxypyrazine 4-oxide in freshly distilledphosphorus oxychloride is refluxed for one hour. Thin layerchromatography indicates that the starting material is no longerpresent. The excess of phosphorus oxychloride is removed in vacuo andthe residue is treated with crushed ice. If decomposition is completethe solution is made alkaline with 10% sodium hydroxide and extractedwith chloroform. The chloroform extracts are washed with water, driedover sodium sulfate and evaporated to give the product which may berecrystallized from a suitable solvent such as ethanol.

Step D: 2-Amino-3-butoxy-6-methoxypyrazine

By replacing the pyrazine and methanol reactants in Preparation 43 byequivalent quantities of 2-amino-3-chloro-6-methoxypyrazine and butanol,respectively, and following substantially the same procedure there isobtained 2-amino-3-butoxy-6-methoxypyrazine.

Replacing the butanol in the above step by another alkanol as methanol,ethanol, propanol and the like, there is obtained the2-amino-3-R-6-methoxypyrazine wherein R is methoxy, ethoxy, propoxy andthe like.

Step E: 2-Chloro-3-butoxy-6-methoxypyrazine

The 2-amino substituent in the product of Step D is converted to the2-hydroxy by reacting a solution of the product of Step D in 6M sulfuricacid at 0°-5° C. with a slight excess of sodium nitrite in water, addingthe sulfuric acid at such a rate the temperature of the reaction mixturedoes not rise above about 5° C. After standing about 45 minutes at 0°-5°C. a little urea is added to destroy excess nitrous acid and the mixtureis treated with sodium hydroxide until strongly basic. The reactionmixture is warmed to 60° C. for an hour, then adjusted to pH 8.5,concentrated to a third of its original volume, and cooled in arefrigerator overnight. The product is separated by filtration, dried invacuo, recrystallized from a suitable solvent yielding2-hydroxy-3-butoxy-6-methoxypyrazine. Treatment of this compound withphosphorus oxychloride by the method of Preparation 13, Step B, gives2-chloro-3-butoxy-6-methoxypyrazine.

The other 2-amino-3-alkoxy-6-methoxypyrazines (described following StepD) when substituted in Step E procedure give

Preparation 82: 2-chloro-3,6-dimethoxypyrazine

Preparation 83: 2-chloro-3-ethoxy-6-methoxypyrazine and

Preparation 84: 2-chloro-3-propoxy-6-methoxypyrazine.

Preparation 85: 2-Chloro-3-phenoxy-6-methoxypyrazine

Step A: 2-Amino-3-phenoxy-6-methoxypyrazine

By replacing the 2,3-dichloropyrazine in Preparation 44 by an equivalentamount of 2-amino-3-chloro-6-methoxypyrazine and following substantiallythe same procedure there is obtained2-amino-3-phenoxy-6-methoxypyrazine.

Step B: 2-Chloro-3-phenoxy-6-methoxypyrazine

The 2-amino substituent of Step A product when treated with sodiumnitrite as described in Step E of Preparation 81 is converted to the2-hydroxy group. Treatment of the 2-hydroxy-3-phenoxy-6-methoxypyrazinewith phosphorus oxychloride by the method of Preparation 13, Step B,gives 2-chloro-3-phenoxy-6-methoxypyrazine.

Preparation 86: 2-Chloro-3-morpholino-6-methoxypyrazine

Step A: 2-Amino-3-morpholino-6-methoxypyrazine

By replacing the 2,3-dichloropyrazine used in Preparation 46 by anequivalent quantity of 2-amino-3-chloro-6-methoxypyrazine and followingsubstantially the same procedure there is obtained2-amino-3-morpholino-6-methoxypyrazine.

Step B: 2-Chloro-3-morpholino-6-methoxypyrazine

The 2-amino substituent of Step A product when treated with sodiumnitrate as described in Step E of Preparation 81 is converted to the2-hydroxy group. Treatment of the2-hydroxy-3-morpholino-6-methoxypyrazine with phosphorus oxychloride byPreparation 13, Step B method, gives2-chloro-3-morpholino-6-methoxypyrazine.

Reaction of any of the other N-heterocycles with2-amino-3-chloro-6-methoxypyrazine by the method of Preparation 86, StepA, followed by the methods of Step B gives the corresponding2-chloro-3-(N-heterocyclic)-6-methoxypyrazine.

ROUTE VII PARTICULARLY SUITABLE WHEN

R is alkyl or phenyl and R³ is alkoxy, phenoxy (or substituted),benzyloxy (or substituted) or N-heterocyclic ##STR15##

The following reactions are typical for the above sequence:

Preparation 87: 2-Bromo-3-methyl-5-methoxypyrazine

Step A: 2,5-Dibromo-3-methylpyrazine

A mixture of 2-hydroxy-3-methyl-5-bromopyrazine and phosphorusoxybromide is heated at about 175° C. for several hours with constantstirring. After hydrolysis of the solution on ice the crude product isextracted with ether and distilled. The distillate is refluxed withphosphorus tribromide for several hours and, after cooling, the solutionis hydrolyzed on ice and the product extracted with ether, the etherremoved in vacuo to give 2,5-dibromo-3-methylpyrazine.

Step B: 2-Bromo-3-methyl-5-methoxypyrazine

By replacing the 2,3-dichloropyrazine used in Preparation 43 by anequivalent quantity of 2,5-dibromo-3-methylpyrazine and followingsubstantially the same procedure, there is obtained a major quantity of2-bromo-3-methyl-5-methoxypyrazine and a small amount of2-methoxy-3-methyl-5-bromopyrazine, which products can be separated bythin layer chromatography on silica gel.

Preparation 88: 2-Bromo-3-phenyl-5-phenoxypyrazine

Step A: 2,5-Dibromo-3-phenylpyrazine

By replacing the 2-hydroxy-3-methyl-5-bromopyrazine used in Step A ofPreparation 87 by an equivalent quantity of2-hydroxy-3-phenyl-5-bromopyrazine and following substantially the sameprocedure there is obtained 2,5-dibromo-3-phenylpyrazine.

Step B: 2-Bromo-3-phenyl-5-phenoxypyrazine

By replacing the 2,3-dichloropyrazine in Preparation 44 by an equivalentquantity of 2,5-dibromo-3-phenylpyrazine and following substantially thesame procedure, there is obtained a major quantity of2-bromo-3-phenyl-5-phenoxypyrazine and a smaller quantity of2-phenoxy-3-phenyl-5-bromopyrazine, the products being separable by thinlayer chromatography on silica gel.

Preparation 89: 2-Bromo-3-ethyl-5-benzyloxypyrazine

Step A: 2,5-Dibromo-3-ethylpyrazine

By replacing the 2-hydroxy-3-methyl-5-bromopyrazine used in Step A ofPreparation 87 by an equivalent quantity of2-hydroxy-3-ethyl-5-bromopyrazine and following substantially the sameprocedure, there is obtained 2,5-dibromo-3-ethylpyrazine.

Step B: 2-Bromo-3-ethyl-5-benzyloxypyrazine

By replacing the 2,3-dichloropyrazine used in Preparation 45 by anequivalent quantity of 2,5-dibromo-3-ethylpyrazine and followingsubstantially the same procedure, there is obtained a major quantity of2-bromo-3-ethyl-5-benzyloxypyrazine and a smaller quantity of2-benzyloxy-3-ethyl-5-bromopyrazine, which products can be separated bythin layer chromatography on silica gel.

Preparation 90: 2-Bromo-3-isopropyl-5-morpholinopyrazine

Step A: 2,5-Dibromo-3-isopropylpyrazine

This compound is prepared by replacing the2-hydroxy-3-phenyl-5-bromopyrazine used in Step A of Preparation 87 byan equivalent quantity of 2-hydroxy-3-isopropyl-5-bromopyrazine.

Step B: 2-Bromo-3-isopropyl-5-morpholinopyrazine

By replacing the 2,3-dichloropyrazine used in Preparation 46 by anequivalent quantity of 2,5-dibromo-3-isopropylpyrazine and followingsubstantially the same procedure there is obtained a major quantity of2-bromo-3-isopropyl-5-morpholinopyrazine and a small amount of2-morpholino-3-isopropyl-5-bromopyrazine, which products can beseparated by thin layer chromatography on silica gel.

By replacing the morpholine employed in Step B of Preparation 90 by anequivalent quantity of any of the other N-heterocycles, there isobtained 2-bromo-3-isopropyl-5-(N-heterocycle)-pyrazine.

ROUTE VIII PARTICULARLY SUITABLE WHEN

R is alkoxy, phenoxy, (or substituted), benzyloxy (or substituted), orN-heterocyclic

R³ is alkoxy, phenoxy (or substituted), benzyloxy (or substituted), orN-heterocyclic, amino or acylamino ##STR16##

The following reactions are typical for the above sequence:

Preparation 91: 2-Chloro-3,5-dimethoxypyrazine

Step A: 2-Amino-3-methoxy-5-bromopyrazine

2-Amino-3,5-dibromopyrazine (7 g.) is boiled for about 9 hours with 0.65g. sodium in 18.5 ml. methanol to give2-amino-3-methoxy-5-bromopyrazine.

Step B: 2-Amino-3,5-dimethoxypyrazine

A mixture of 0.1 mole of 2-amino-3-methoxy-5-bromopyrazine and 0.1 moleof sodium in 160 ml. of anhydrous methanol is refluxed 5- 10 hours andpoured into water. The product is extracted with ether or chloroform andrecrystallized from a suitable solvent such as ethanol to give2-amino-3,5-dimethoxypyrazine.

Step C: 2-Hydroxy-3,5-dimethoxypyrazine

A solution of 2-amino-3,5-dimethoxypyrazine (0.02 mole) in 300 ml. of 6Msulfuric acid at 0°-5° C. is treated with 0.022 mole sodium nitrite in25 ml. of water at such a rate to insure that the temperature of thereaction mixture does not rise above 5° C. After standing 45 minutes at0°-5° C., a little urea is added to destroy excess nitrous acid and themixture then is treated with sodium hydroxide solution until stronglybasic. The reaction mixture is warmed to 60° C. for one hour and thenbrought to pH 8.5. The mixture is concentrated to a third of theoriginal volume and cooled in the refrigerator overnight. The product isseparated by filtration and dried in vacuo, recrystallized from asuitable solvent to give 2-hydroxy-3,5-dimethoxypyrazine.

Step D: 2-Chloro-3,5-dimethoxypyrazine

Treatment of the above-obtained 2-hydroxy-3,5-dimethoxypyrazine withphosphorus oxychloride by the method described in Preparation 13, StepB, gives 2-chloro-3,5-dimethoxypyrazine.

Replacement of the methanol employed in Steps A and B of Preparation 91with an equivalent quantity of ethanol, propanol, butanol or other loweralkanol and following substantially the same methods described in thepreceding procedure there is obtained the corresponding2-chloro-5-(ethoxy, propoxy, butoxy)-5-methoxypyrazine.

Preparation 92: 2-Chloro-3,5-dimorpholinopyrazine

Step A: 2-Amino-3-morpholino-5-bromopyrazine

2-Amino-3,5-dibromopyrazine is reacted with morpholine at 130° C. underpressure yielding 2-amino-3-morpholino-5-bromopyrazine.

Step B: 2-Amino-3,5-dimorpholinopyrazine

A mixture of the above-obtained 2-amino-3-morpholino-5-bromopyrazine(0.04 mmole), morpholine (0.07 mmole) and 50 ml. of dimethylformamideare heated at 100°-140° C. for about 3 to 5 days in an atmosphere ofnitrogen. The reaction mixture is cooled and evaporated to dryness at awater bath temperature of 55° C. A chloroform solution of the residue isextracted twice with 0.1M sodium hydroxide, dried over magnesium sulfateand evaporated to leave 2-amino-3,5-dimorpholinopyrazine.

Step C: 2-Chloro-3,5-dimorpholinopyrazine

This product is obtained by treating the2-amino-3,5-dimorpholinopyrazine with sodium nitrite by the methoddescribed in the preceding procedure, Step C, and then with phosphorusoxychloride by the method described in Preparation 13, Step B.

Preparation 93: 2-Chloro-3-morpholino-5-aminopyrazine

Step A: 2-Hydroxy-3-morpholino-5-bromopyrazine

2-Amino-3-morpholino-5-bromopyrazine (see Preparation 92, Step A) istreated with sodium nitrite by the method described in Preparation 91,Step C, to give 2-hydroxy-3-morpholino-5-bromopyrazine.

Step B: 2-Hydroxy-3-morpholino-5-aminopyrazine

A mixture of 2-hydroxy-3-morpholino-5-bromopyrazine (1 g.) in 100 ml. ofconcentrated ammonium hydroxide is heated overnight at 100°-140° C. in asealed tube to give 2-hydroxy-3-morpholino-5-aminopyrazine.

Step C: 2-Chloro-3-morpholino-5-aminopyrazine

Treatment of the 2-hydroxy-3-morpholino-5-aminopyrazine with phosphorusoxychloride by the method described in Preparation 13, Step B, gives thedesired 2-chloro-3-morpholino-5-aminopyrazine.

Preparation 94: 2-Chloro-3-morpholino-5-phenoxypyrazine

Step A: 2-Amino-3-morpholino-5-phenoxypyrazine

A suspension of 0.1 mole of sodium phenoxide and 0.1 mole of2-amino-3-morpholino-4-bromopyrazine is refluxed 10- 20 hours. Thecooled mixture is extracted with diethyl ether, washed with cold 2Nsodium hydroxide solution, dried and evaporated to give2-amino-3-morpholino-5-phenoxypyrazine.

Step B: 2-Chloro-3-morpholino-5-phenoxypyrazine

Upon treatment of the 2-amino-3-morpholino-5-phenoxypyrazine with nitricacid by the method described in Preparation 91, Step C, there isobtained the corresponding 2-hydroxy-compound which when treated withphosphorus oxychloride by the method described in Preparation 13, StepB, gives the desired 2-chloro-3-morpholino-5-phenoxypyrazine.

Preparation 95: 2-Chloro-3-morpholino-5-benzyloxypyrazine

Step A: 2-Amino-3-morpholino-5-benzyloxypyrazine

Sodium hydride (0.1 mole) is added to benzyl alcohol (0.1 mole) in 100ml. dry benzene and the mixture is refluxed one to two hours. The cooledsolution is treated with 0.1 mole of2-amino-3-morpholino-5-bromopyrazine in 100 ml. of benzene and theresulting mixture refluxed for 20-60 hours whereupon it is cooled,washed with water, dried and evaporated to give2-amino-3-morpholino-5-benzyloxypyrazine.

Step B: 2-Chloro-3-morpholino-5-benzyloxypyrazine

Upon treatment of the 2-amino-3-morpholino-5-benzyloxypyrazine withnitric acid by the method described in Preparation 91, Step C, there isobtained the corresponding 2-hydroxy- compound which upon treatment withphosphorus oxychloride by the method described in Preparation 13, StepB, gives 2-chloro-3-morpholino-5-benzyloxypyrazine.

PREPARATION OF THE PYRAZINE END PRODUCTS, I

The following examples will illustrate representative products of thisinvention by the reaction of a 2-chloropyrazine with a5-hydroxymethyloxazolidine or by the reaction of a 2-hydroxypyrazinewith a 5-sulfonyloxymethyloxazolidine compound. A representative exampleproviding typical reaction conditions for each of these methods follows.While the table indentifying representative end products shows theirpreparation by reacting a 2-chloropyrazine with a5-hydroxymethyloxazolidine, it is to be understood that thecorresponding 2-hydroxypyrazine (the preparation of which is alsoincluded in the preceding discussion) can as well be reacted with the5-sulfonyloxymethyloxazolidine to provide the same end product andpreparation by this alternative method is to be understood as beingincluded for each product identified.

EXAMPLE 1 S-(-)-2-(3-tert-butylamino-2-hydroxypropoxy)-3-phenylpyrazinehydrogen maleate

A mixture of S-2-phenyl-3-tert-butyl-5-hydroxymethyloxazolidine (540mg., 2 mmoles plus 15% excess), 2-chloro-3phenylpyrazine (382 mg., 2mmoles) and potassium tert-butoxide (224 mg., 2 mmoles) in tert-butanol(3 ml.) are permitted to stand 6 days at ambient temperature. Thesolution then is evaporated to dryness, the residue treated with Nhydrochloric acid (4 ml.) and stirred 75 minutes at 55°-65° C. Themixture is cooled, extracted with diethyl ether, and the aqueous layertreated with excess potassium carbonate until the solution is stronglybasic. The mixture is extracted with diethyl ether and evaporation ofthe ether extracts gives 557 mg. of a light yellow oil. Thin layerchromatography (TLC) showed the presence of a single compound which gavean R_(f) value that differed from that of starting material. The oil isdissolved in ethyl acetate (10 ml.) and treated with maleic acid (215mg.) in ethyl acetate (9 ml.) to give 570 mg. ofS-(-)-2-(3-tert-butylamino-2-hydroxypropoxy)-3-phenylpyrazine hydrogenmaleate, m.p. 136.0°-138.5° C. Recrystallization from a mixture ofmethanol and ethyl acetate and drying in vacuo provides 485 mg. ofproduct, m.p. 137.5°-139.0° C., [α]_(D) ²⁵ -5.205 (C = 3%, CH₃ OH).

Analysis calculated for C₁₇ H₂₂ O₂ N₃.C.sub. 4 H₄ O₄ : C, 60.42; H,6.52; N, 10.07; Found: C, 60.10; H, 6.68; N, 10.25.

EXAMPLE 2S-(-)-2-(3-tert-butylamino-2-hydroxypropoxy)-3-n-propylpyrazine hydrogenmaleate

S-3-tert-butyl-5-(p-toluenesulfonyloxymethyl)oxazolidine (Preparation 5)(10 mmole) are dissolved in benzene (12 ml.) and tetrahydrofuran (0.9ml.). The sodium salt of 2-hydroxy-3-n-propylpyrazine (10 mmole) isadded and the mixture refluxed for about 20 hours. The reaction mixturethen is extracted with 3 10-ml. portions of 1N hydrochloric acid and theaqueous layer then made alkaine with ammonia and extracted with 3 10-ml.portions of benzene. The combined benzene extracts are dried andevaporated to giveS-(-)-2-(3-tert-butylamino-2-hydroxypropoxy)-3-n-propylpyrazine. Thisproduct is converted to the hydrogen maleate salt by treatment withmaleic acid in tetrahydrofuran by substantially the same proceduredescribed in Example 1.

Any other 5-R⁵ -oxymethyl-2-R⁶ -3-R¹ -oxazolidine starting substance(III) can be substituted for the oxazolidines employed in Examples 1 and2 for reaction with the desired pyrazine (II) to provide end product I.The following table identifies representative novel S-2-(3-R¹-amino-2-hydroxypropoxy)-3-R,5-R³ -6-R² -pyrazine compounds fallingwithin the scope of this invention which are prepared by the method ofeither Example 1 or 2.

                                      TABLE VI                                    __________________________________________________________________________     ##STR17##                                                                     ##STR18##                                                                    Sinister                                                                       Ex.                                                                          No.      R.sup.3  R.sup.2 R        R.sup.1     R.sup.6                        __________________________________________________________________________     3       H        H       propyl   t-butyl     H                               4       H        H       methyl   t-butyl     i-propyl                        5       H        H       ethyl    1-methyl-2- H                                                                 phenethyl                                   6       H        H       i-propyl 1-methyl-2-(3-                                                                            H                                                                 inodolyl)ethyl                              7       H        H       phenyl   t-butyl     H                               8       H        H       phenyl   i-propyl    phenyl                          9       H        H       methyl   3-(2,2-dimeth-                                                                            phenyl                                                            yl)propyl                                  10       H        H       phenyl   1,1-dimethyl-                                                                 2-hydroxyethyl                             11       H        H       ethyl    1,1-dimethyl-                                                                             phenyl                                                            2-phenethyl                                12       H        H       ethyl    1,1-dimethyl-                                                                             phenyl                                                            2-(3-indolyl)-                                                                ethyl                                      13       H        H       ethyl    2,2-dimethyl-                                                                             phenyl                                                            2-(3-indolyl)-                                                                ethyl                                      14       H        H       p-methoxy-                                                                             t-butyl     phenyl                                                   phenyl                                              15       H        H       p-methyl-                                                                              t-butyl     phenyl                                                   phenyl                                              16       H        H       cyclo-   1,1-dimethyl-                                                                             H                                                        pentyl   propargyl                                  17       H        H       p-nitro- t-butyl     phenyl                                                   phenyl                                              18       H        H       p-amino- t-butyl     phenyl                                                   phenyl                                              19       methyl   H       methyl   t-butyl     phenyl                         20       methyl   methyl  methyl   t-butyl     phenyl                         21       phenyl   H       methyl   t-butyl     phenyl                         22       phenyl   methyl  propyl   t-butyl     phenyl                         23       methyl   phenyl  propyl   t-butyl     phenyl                         24       methyl   methyl  phenyl   t-butyl     phenyl                         25       H        H       p-hydroxy-                                                                             i-propyl    H                                                        phenyl                                              26       H        H       p-methoxy-                                                                             2-hydroxyethyl                                                                            H                                                        phenyl                                              27       H        H       p-chloro-                                                                              t-butyl     H                                                        phenyl                                              28       methyl   H       p-hydroxy-                                                                             t-butyl     H                                                        phenyl                                              29       methyl   methyl  benzyl   t-butyl     H                              30       H        H       cyclohexyl                                                                             t-butyl     H                              31       H        H       benzyl   t-butyl     phenyl                         32       phenyl   phenyl  benzyl   t-butyl     phenyl                         33       phenyl   H       phenyl   t-butyl     phenyl                         34       p-methyl-                                                                              H       phenyl   t-butyl     phenyl                                  phenyl                                                               35       p-methoxy-                                                                             H       phenyl   t-butyl     phenyl                                  phenyl                                                               36       p-chloro-                                                                              H       phenyl   t-butyl     phenyl                                  phenyl                                                               37       p-nitro- H       phenyl   t-butyl     phenyl                                  phenyl                                                               38       o-hydroxy-                                                                             H       phenyl   t-butyl     phenyl                                  phenyl                                                               39       m-hydroxy-                                                                             H       phenyl   t-butyl     phenyl                                  phenyl                                                               40       p-hydroxy-                                                                             H       phenyl   t-butyl     phenyl                                  phenyl                                                               41       cyclohexyl                                                                             H       benzyl   2-hydroxyethyl                                                                            H                              42       cyclopentyl                                                                            H       benzyl   2-hydroxyethyl                                                                            H                              43       cyclohexyl                                                                             cyclo-  phenyl   t-butyl     H                                                hexyl                                                       44       pyridyl  pyridyl methyl   t-butyl     H                              45       H        H       methoxy  t-butyl     phenyl                         46       H        H       phenoxy  t-butyl     phenyl                         47       H        H       benzyloxy                                                                              t-butyl     phenyl                         48       H        H       morpholino                                                                             t-butyl     phenyl                         49       H        H       1-pyrroli-                                                                             t-butyl     phenyl                                                   dinyl                                               50       H        H       piperidino                                                                             t-butyl     phenyl                         51       H        H       hexahydro-                                                                             t-butyl     phenyl                                                   azepinyl                                            52       H        H       pyrazolyl                                                                              t-butyl     phenyl                         53       H        H       imidazolyl                                                                             t-butyl     phenyl                         54       H        H       triazolyl                                                                              t-butyl     phenyl                         55       H        H       thiomorph-                                                                             t-butyl     phenyl                                                   olino                                               56       methyl   methyl  morpholino                                                                             t-butyl     phenyl                         57       phenyl   phenyl  morpholino                                                                             t-butyl     phenyl                         58       methyl   H       methyl   t-butyl     phenyl                         59       ethyl    H       methyl   t-butyl     phenyl                         60       methyl   H       phenyl   t-butyl     phenyl                         61       phenyl   H       methyl   t-butyl     phenyl                         62       p-chloro-                                                                              H       methyl   t-butyl     phenyl                                  phenyl                                                               63       p-bromo- H       methyl   t-butyl     phenyl                                  phenyl                                                               64       methyl   H       methyl   t-butyl     phenyl                         65       methoxy  H       phenyl   t-butyl     phenyl                         66       p-nitro- H       methyl   t-butyl     phenyl                                  phenyl                                                               67       p-dimeth-                                                                              H       methyl   t-butyl     phenyl                                  ylamino-                                                                      phenyl                                                               68       cyclohexyl                                                                             H       methyl   t-butyl     phenyl                         69       4-pyridyl                                                                              H       methyl   t-butyl     phenyl                         70       3-pyridyl                                                                              H       phenyl   t-butyl     phenyl                         71       H        methyl  methyl   t-butyl     phenyl                         72       H        methyl  phenyl   t-butyl     phenyl                         73       methyl   H       propoxy  t-butyl     phenyl                         74       ethyl    H       phenoxy  t-butyl     phenyl                         75       methyl   methyl  benzyloxy                                                                              t-butyl     phenyl                         76       phenyl   H       morpholino                                                                             t-butyl     phenyl                         77       methoxy  H       piperidino                                                                             t-butyl     phenyl                         78       methyl   H       hexahydro-                                                                             t-butyl     phenyl                                                   azepinyl                                            79       phenyl   H       imidazolyl                                                                             t-butyl     phenyl                         80       ethyl    H       thiomorph-                                                                             t-butyl     phenyl                                                   olino                                               81       methyl   H       triazolyl                                                                              t-butyl     phenyl                         82       H        methoxy butoxy   t-butyl     phenyl                         83       H        methoxy methoxy  t-butyl     phenyl                         84       H        methoxy ethoxy   t-butyl     phenyl                         85       H        methoxy propoxy  t-butyl     phenyl                         86       H        methoxy phenoxy  t-butyl     phenyl                         87       H        methoxy morpholino                                                                             t-butyl     phenyl                         88       methoxy  H       methyl   t-butyl     phenyl                         89       phenoxy  H       phenyl   t-butyl     phenyl                         90       benzyloxy                                                                              H       ethyl    t-butyl     phenyl                         91       morpholino                                                                             H       i-propyl t-butyl     phenyl                         92       methoxy  H       methoxy  t-butyl     phenyl                         93       morpholino                                                                             H       morpholino                                                                             t-butyl     phenyl                         94       amino    H       morpholino                                                                             t-butyl     phenyl                         95       phenoxy  H       morpholino                                                                             t-butyl     phenyl                         96       benzyloxy                                                                              H       morpholino                                                                             t-butyl     phenyl                         __________________________________________________________________________

We claim:
 1. A pyrazine compound having the structure ##STR19## or apharmacologically acceptable salt thereof wherein R representsmorpholino or thiomorpholino;R¹ represents a straight or branched chainC₃₋₆ alkyl, a straight or branched chain hydroxy substituted C₃₋₆ alkyl,a straight or branched chain C₃₋₆ alkinyl, phenyl-C₁₋₆ alkyl oriodolyl-C₁₋₆ alkyl; R² and R³ can represent the same or differentsubstituents and represent hydrogen, C₁₋₃ alkyl, C₅₋₇ cycloalkyl, C₁₋₃alkoxy, phenoxy, phenyl, substituted phenyl wherein the substituent isC₁₋₃ alkyl, C₁₋₃ alkoxy, amino, acetylamino, nitro or halo; ormorpholino or thiomorpholino.
 2. A pyrazine compound as claimed in claim1 wherein R² and R³ are each hydrogen.
 3. A pyrazine compound of claim 1wherein R² and R³ are each hydrogen, and R is morpholino.
 4. A pyrazinecompound of claim 1 wherein R² and R³ are each hydrogen and R¹ is astraight or branched chain C₃₋₆ alkyl.
 5. A pyrazine compound as claimedin claim 4 wherein R¹ is tert-butyl.
 6. A pyrazine compound of claim 1wherein R is thiomorpholino.
 7. A pyrazine compound as claimed in claim1 wherin R is morpholino.
 8. A pyrazine compound as claimed in claim 1wherein R² is hydrogen.
 9. A pyrazine compound as claimed in claim 1wherein R³ is hydrogen.